MULTISTEP SIGNALING REQUIREMENTS FOR PITUITARY ORGANOGENESIS IN-VIVO

During development of the mammalian pituitary gland specific hormone-p roducing cell types, critical in maintaining homeostasis, emerge in a spatially and temporally specific fashion from an ectodermal primordiu m. We have investigated the molecular basis of generating diverse pitu itary cell phenotypes from a common precursor, providing in vivo and i n vitro evidence that their development involves three sequential phas es of signaling events and the action of a gradient at an ectodermal b oundary. In the first phase, the BMP4 signal from the ventral dienceph alon, expressing BMP4, Wnt5a, and FGF8, represents a critical dorsal n euroepithelial signal for pituitary organ commitment in vivo. Subseque ntly, a BMP2 signal emanates from a ventral pituitary organizing cente r that forms at the boundary of a region of oral ectoderm in which Shh expression is selectively excluded. This BMP2 signal together with a dorsal FGF8 signal, appears to create opposing activity gradients that are suggested to generate overlapping patterns of specific transcript ion factors underlying cell lineage specification events, whereas Wnt4 is needed for the expansion of ventral pituitary cell phenotypes. In the third phase, temporally specific loss of the BMP2 signal is requir ed to allow terminal differentiation. The consequence of these sequent ial organ and cellular determination events is that each of the hormon e-producing pituitary cell types-gonadotropes, thyrotropes, somatotrop es, lactotropes, corticotropes, and melanotropes-appear to be determin ed, in a ventral-to-dorsal gradient, respectively.